Specific delivery of drugs and pharmaceutical compositions to the colon is important in the treatment of a wide variety of diseases and conditions. Targeting of drugs to the colon provides the ability to locally treat large bowel diseases, thus avoiding systemic effects of drugs or inconvenient and painful transcolonic administration of drugs. Furthermore, there is an increased need for delivery to the colon of drugs that are reported to be absorbable in the colon, such as steroids, which would increase the efficiency and enable to reduce the required effective dose Godbillon, J., et al., Br. J. Clin. Pharmacol. 19:113S (1985); Antonin, K. H. et al., Br. J. Clin. Pharmacal. 19:137S (1985); Fara, J. W., 3rd International Conference on Drug Absorption, Edinburgh (1988); for a review see Rubinstein, A., Biopharm. Drug Dispos. 11:465-475 (1990)).
However, the targeting of drugs to desired locations in the alimentary canal can be complicated. Because of its location at the distal portion of the alimentary canal, the colon is particularly difficult to access. The design of orally administered colonic delivery systems must take into account factors such as the pH of the alimentary canal and the presence of enzymes in the stomach and small intestine.
In current techniques for targeting drugs to the colon, solid formulations of the desired drug molecules are coated with a pH resistant polymeric coating. Such formulations are similar to enteric coated formulations which may be used to deliver drugs to the distal ileum. Enteric coatings include bioerodable polymers such as shellac and cellulose acetate phthalate. (Levine et al., Gastroenterology 92:1037-1044 (1987)).
In contrast to the enteric coated formulations, however, the formulations for colonic delivery are designed to withstand both low and slightly basic pH values (around seven) for several hours. During this time, they are assumed to pass the stomach and the small intestine and reach the large intestine, where the coat disintegrates and the drug release process is initiated. In this way, drugs such as 5-amino salicylic acid (5-ASA), and some steroids have been delivered to the colon.
The polymers used for this purpose are commonly acrylic acid derivatives or cellulose derivatives such as cellulose acetate phthalate, or ethyl cellulose (Rasmussen, S. N., et al., Gastroenterology 83:1062 (1982); Levine, D. S., et al., Gastroenterology 92:1037 (1987)); Mardini H., et al., Gut 28:1084-1089 (1987). However, an important limitation of this technique is the uncertainty of the location and environment in which the coat starts to degrade. Depending upon the gastrointestinal motility pattern, which can vary widely in individual patients and in different disease states, degradation of the coating can occur deep in the colon, or within the small intestine.
The presence of short chain fatty acids, carbon dioxide, and other fermentation products, and residues of bile acids, often reduce the pH of the colon to approximately six (Stevens, C. E., Amer. J. Clin. Nutr. 31:S161 (1978); McNeil, N. I., et al., Gut 28:707 (1987)). This change in pH calls into question the reliance on higher colonic pH as a trigger. U.S. Pat. No. 4,627,850 (Deters et al.) discloses an a osmotic capsule for the controlled rate delivery of a drug comprising outer and inner walls each formed of a different polymeric material, the inner wall defining a space containing the drug, with a passageway through the walls connecting the exterior of the outer wall with the interior of the inner wall. U.S. Pat. No. 4,904,474 (Theeuwes et al) discloses a colonic drug delivery device comprising means for delaying the delivery in the drug and in the small intestine and means for delivering the drug in the colon. This device comprises osmotic means for forcing the active pharmaceutical agent out from the compartment in which it is contained through an exit provided in said compartment, into the colon. The means for delaying delivery in the stomach or in the small intestine are practically pH resistant coatings. The delay in delivery of the drug is time based, the structure is so calculated that the contents of the inner drug-filled space are not forced out before the device has reached the preselected target region of the gastro-intestinal tract. One of the drawbacks of these devices is that in case the travel of the device in the GI tract is delayed in a certain portion of the tract, for example due to mechanical reasons, the drug will still be released after the predetermined time has passed, irrespective of the fact that the target region has not been reached.
The ability of the colonic flora to degrade substrates that are resistant to small bowel digestion has been studied as an alternative method for colonic delivery of drugs. This principle was utilized to deliver laxative products, mainly sennoside and related compounds. Concentrated senna extract contains anthracene derivatives which exist in the form of glycosides and can be hydrolyzed to anthroquinones, anthranols, and oxanthrones. The sennosides are much more effective as laxatives when administered intact, compared to the sugar-free aglycones, probably because the sugar moiety provides protection against chemical breakdown in the small intestine (Fairbairn, J. W., J. Pharm. Pharmacol. 1:683 (1949)). Hardcastle and Wilkins demonstrated that when sennosides were directly administered to the colon, no laxative activity was observed as compared to administration of the same compounds previously incubated with feces or E. coli. It was postulated that bacteria liberate the free anthraquinones, which then promote colonic peristalsis via a local effect on the mysenteric plexus (Hardcastle, J. D., et al., Gut 11:1038 (1970); Cummings, J. H., Gut 15:758 (1974)).
Bacteria can also act on the phenolic laxative sulisatin, in which two of the phenols are esterified with sulfate. The lack of arylsulfatase activity in the small intestinal mucosa allows the drug to pass intact to the colon, where bacteria convert it to the active hydroxy and dihydroxy derivatives. This is in contrast to the acetate ester of the diphenylmethane derivative bisacodyl, which is readily cleaved by the esterases in the small intestine to an active metabolite, which in turn stimulates water and electrolyte secretion from the colonic mucosa and results in laxation (Cummings, J. H., Gut 15:758 (1974); Moreto, M., et al., Arzneim. Forsch./Drug Res. 29:1561 (1979); Gullikson, G. W., et at., in Pharmacology of Intestinal Permeation II, Csaky, T. Z. (ed.), Springer-Verlag, Heidelberg, p. 419 (1984)).
Simpkins and co-workers recently compared the ability of the narcotic antagonists naloxone and nalmefene with their glucuronide conjugates to induce diarrhea in morphine-dependent rats. (In these animals the brain is sensitive to narcotic antagonists, and the animals are useful in the bioassay of the systemic delivery of narcotic antagonists intended for local colonic release.) Oral administration of the two drugs caused diarrhea, withdrawal behavior and tail skin temperature response within 15 minutes, while with the glucuronide conjugates of either of the narcotic antagonists diarrhea was delayed for 1 to 3 hours, reflecting the transit time to the distal ileum. Direct colonic administration of the naloxone and nalmefene glucuronides caused diarrhea with 5-8 minutes. It was suggested that the pharmacologic response to the glucuronide conjugates of naloxone and nalmefene was initiated by bacterial .beta.-glucuronidases in the rat colon. This hydrolysis of the drug glucuronides was found to be specific to bacterial activity in the colon, because the glucuronides were inactive when administered subcutaneously (Simpkins, J. W., et al., J. Pharmacol. Exp. Ther. 244:195 (1988)).
A drug traditionally used in the treatment of inflammatory bowel disease is sulfasalazine. Sulfasalazine is composed of the antibacterial sulfapyridine linked to the anti-inflammatory 5-ASA with an azo bond. When the drug was first introduced in 1941, the sulfa moiety was regarded as the major therapeutic determinant in the action of sulfasalazine. It was later recognized that the 5-ASA is responsible for the clinical effect, while the sulfapyridine causes most of the side effects of the drug (Khan, A. K., et al., Lancet 2:892 (1977)). In fact, the sulfasalazine is a prodrug which carries the active 5-ASA to the colon, where bacterial azo reduction releases the molecule with the desired therapeutic properties (Klotz, U., Clin. Pharmacokin 10:285 (1985)).
Based on the understanding of the mode of action of sulfasalazine, a second generation of the sulfasalazine has been developed: azodisalicylate and salicylazobenzoic acid. Azodisalicylate is composed of two 5-ASA molecules in which the amino groups of the two molecules are linked through an azo group. When it is reduced by colonic bacteria, the azodisalicylate delivers twice the amount of 5-ASA, and avoids the undesired action of the sulfapyridine (Willoughby, C. P., et al., Gut 23:1081 (1982); Bartalsky, A., Lancet 1:960 (1982)).
The 5-ASA prodrugs, including sulfasalazine, azodisalicylate and salicylazobenzoic acid, represent a slightly different approach from the classic prodrug delivery concept in that release of the parent drug is mediated by bacterial enzymes located at the target organ, rather than by enzymes of the target tissues. The realization that enzymes characteristic of inhabitant microorganisms of the colon may convert prodrugs and other molecules to active therapeutics led to an increase in research activity in the area of microbially controlled drug delivery to the colon.
A modified method to deliver 5-ASA to the colon was reported by Brown, Parkinson and co-workers who, in order to eliminate the effects of the sulfapyridine fraction, azo-linked sulfasalazine to a high molecular weight polymeric backbone. The resulting water-soluble polymer was shown to release 5-ASA in the presence of anaerobic rat cecal bacterial.
Pharmacokinetic analysis of 5-ASA levels following the polymeric prodrug administration showed similar deliveries of 5-ASA and metabolites to the lower bowel, blood, and urine of orally dosed rats. Pharmacodynamic analysis showed that the polymer also decreased the carrageenan-induced ulcerative-colitis-like inflammatory response in guinea pigs, based on quantitative histopathological results. This pharmacodynamic response was found to be equal to the one achieved after direct administration of 5-ASA and superior to sulfasalazine (Brown, J. P., et al., J. Med. Chem. 26:1300 (1983)).
Friend and Chang glycosylated selected steroid drugs commonly used in the treatment of inflammatory bowel disease (hydrocortisone, prednisolone, dexamethasone, and fluorocortisone). Glycosylation was accomplished using galactose, glucose, and cellobiose which are known to serve as substrates for colonic bacteria (Cummings, J. H., et al., Amer. J. Clin. Nutr. 45:1243 (1987)). The glycoside prodrugs were incubated with homogenates of the contents of various regions of the rat alimentary canal. In the stomach, proximal ileum, and distal ileum, it was found that the rate of hydrolysis of all prodrugs was relatively slow. However, the rate of hydrolysis was higher in homogenates of the contents of the cecum.
The authors concluded that delivery of glycoside prodrugs to the colon depends upon the different rates of hydrolysis in the various segments of the alimentary canal, the different transit times in those segments, and the octanol/water partition coefficient of the prodrugs. Thus, the faster transit in the upper GI tract coupled with its slow observed degradation activity, and the slow transit in the cecum, in which relatively faster degradation occurs, suggest the potential use of glycoside prodrugs to treat large bowel disease (Friend, D. R., et at., J. Med. Chem. 28:51 (1985)).
The covalent functionality of azoaromatic compounds, susceptible to cleavage by the colonic bacteria, was recently utilized by Saffran and co-workers (Saffran, M., et al., Science 233:1081 (1986); Saffran, M., et al., J. Pharm. Sci. 77:33 (1988)). Assuming that the distal part of the small bowel and the colon are the preferred sites for intestinal absorption of protein drugs, insulin and lysine-vasopressin solid dosage forms (pellets and gelatin minicapsules) were coated with copolymers of styrene and hydroxyethylmethacrylate cross-linked with divinylazobenzene.
It was postulated that this polymer is able to protect the entrapped protein drugs against the digestive enzymes of the stomach and the upper portion of the small intestine, and that the polymer is degraded upon arrival at the colon. Indeed, when incubated in fecal content of rat or human for eight days, perforation of the polymer coat was microscopically detected. In addition, sustained pharmacological response of the protein drugs, antitiuresis for lysine-vasopressin, and hypoglycemia for insulin, was observed when the coated delivery systems were orally administered to rats, and later to dogs (Saffran, M., et al., Diabetes 38S:81A (1989)).
A delivery system of antiamoebic drug, relying on specific phagocytosis of the carrier by Entamoeba histolytica, which is confined to the lumen of the large intestine, has been reported (Mirelman, D., et al., J. Infect. Dis. 159(2):303 (1989)). Small silica particles covalently linked to nitroimidazole-based drug were designed to eliminate the parasite from the lumen of diseased humans. It was found that E. histolytica trophozoites avidly phagocytosed the tiny particles and released the bound drug, causing rapid cell death of the trophozoites both in vitro, and in vivo in hamsters. Although the amount of digested particles did not exceed 5% of the total number of particles, it was stated that this was enough to cause the death of most of the trophozoites population in 24 hours. In the absence of amoebic trophozoites, no significant release of the covalently bound drug was observed.
While there is evidence that certain proteins and peptides such as interleukin-II, interferon, colony-stimulating factor, tumor necrosis factor, and melanocyte-stimulating hormone may create new and effective therapies for diseases that are now poorly controlled, the acceptance of these proteins as drugs is currently limited by the methods of delivery. Colonic delivery may be a preferred route of administration for these and other new protein and peptide drugs.
Colonic delivery is also important for targeting drugs to the colon, particularly for the treatment of inflammatory bowel disease (IBD) and ulcerative colitis. However, the currently available enterally administered preparations of drugs designed for colonic delivery are not feasible for long-term use in humans, in part because of the potential toxicity of the azo compounds. These exists a need for an improved colonic delivery system that can be used with a wide variety of drugs and bioactive compounds.